Scientists rethink hormone therapy to prevent dementia

FORT WORTH — One by one, scientific studies have obliterated the notion that hormone replacement therapy can prevent or delay certain diseases in post-menopausal women.

A decade ago, the landmark Women’s Health Initiative shot down the idea that taking daily doses of estrogen and progestin would protect women from coronary heart disease, strokes and dementia.

Two years later, in 2004, a follow-up study suggested hormone therapy actually had an adverse effect on cognitive functions in women age 65 to 79. Taking female hormones in hopes of delaying the onset of Alzheimer’s disease, for example, was quickly discouraged by doctors.

Yet dozens of top scientists gathered at the Renaissance Worthington Hotel here last week to pick apart those findings and even advance a theory that a “window of opportunity” exists for women who want to use hormone replacement to maintain their brain function after menopause. The conference was sponsored by the National Institutes of Health and the National Institute on Aging.

“We need to understand why estrogen can have positive affects on memory in younger women but if you alter the parameters, it is negative,” said Heather Bimonte-Nelson, a researcher at Arizona State University in Phoenix.

The scientists are hoping to discover a timeframe — possibly lasting several years or longer — when women might experience the protective effects of using hormone supplements.

“Estrogen has to be used within a certain window for it to have its good effect,” Bimonte-Nelson stressed.

The scientists are targeting a period called perimenopause, also known as menopausal transition, when a woman’s body makes a natural shift from regular cycles of ovulation and menstruation toward permanent infertility, or menopause.

Although menopause is a natural biological process, signaling a loss of estrogen, women have been using replacement hormones since the 1950s, primarily to fight hot flashes, vaginal dryness and disrupted sleep.

As hormone replacement became more widely used, medical experts came to believe the compounds also were keeping women healthier and actually protecting them from life’s most crippling and deadly diseases. However, there was no scientific proof.

Following the 2002 release of the landmark hormone report, most American women stopped taking the drugs. Doctors now advise them to take the smallest possible dose of estrogen, and possibly progestin, to relieve menopausal symptoms, but for no longer than five years.

The “critical window hypothesis” has evolved as scientists searched for ways to maintain brain health in aging women, said Pauline Maki, a researcher at the University of Illinois at Chicago.

“Alzheimer’s disease is the country’s most pressing disease,” she said.

An estimated 5.4 million Americans of all ages have Alzheimer’s, although the vast majority is over 65, according to the Alzheimer’s Association, a national advocacy group. The disease is expected to escalate rapidly in coming years as the baby boom generation ages. It also will affect more women because of their increased life expectancy relative to males.

The researchers said they cannot reject the long-known beneficial effects of estrogen on younger women.

“Animal studies say estrogen is good for the brain. Clinical studies in women have shown the cognitive and cardiac benefits of estrogen as well,” said James W. Simpkins, a professor of pharmacology and neuroscience at the University of North Texas Health Science Center.

“We need to know what happens when a woman loses estrogen during menopause. Is it good for her or bad for her?” he said. “That’s what we’re arguing over.”

The conference turned a critical eye on the findings of the Women’s Health Initiative, which began in 1993 and enrolled over 160,000 postmenopausal women.

One of the initiative’s findings did suggest a benefit from using hormone replacement. It found a 34 percent reduction in hip fracture risk among women taking estrogen plus progestin compared with women of a similar age who were not taking this drug.

Still, several researchers called the 2004 memory study poorly designed because hormones were given primarily to older women, who might already have been suffering the effects of early dementia. Women taking hormones closer to the start of menopause, between ages 50 to 55, might have had a better outcome, they argued.

“The study taught us some very important things, such as you don’t treat a 65-year-old woman with estrogen to improve her memory,” said Meharvan Singh, chairman and professor of pharmacology and neuroscience at UNT.

“But what about treating younger women who are going through menopause in their 50s but with other hormone formulations?” he said.

Mark A. Espeland, a researcher at Wake Forest University, defended the findings of the study, which found women who had received daily doses of estrogen and progestin had a “slightly but significantly lower” average cognitive function compared with women who took a placebo.

“It was a very well-designed and well-conducted study,” said Espeland, who helped design it and was the lead author. “I understand the criticism, but I think the study has done quite a bit to change the conversation about hormone replacement therapy.”

Even as they pushed the idea of using estrogen replacement to protect against dementia, the researchers acknowledged many unknowns. They have yet to figure out when this “protective window” might start, which hormones should be used and in what form, and how long they could be administered before their effects turn negative.

Singh, who co-chaired the conference with Simpkins, said the answers will take time because future estrogen studies will be smaller and more incremental than the massive Women’s Health Initiative, which was estimated to cost the federal government between $700 million and $1 billion.

“The goal here is to give informed therapeutic options to women,” Singh said. “But first, we have to understand what effect these hormones have on the brain and when they might be beneficial.”

TIMELINE: Women’s Health Initiative

1991 — The National Institutes of Health announces plans to undertake the largest study ever to look at women and menopause. The trials will measure low-fat dietary patterns, calcium and vitamin D supplementation and two studies of hormone use in women after menopause and their possible effect on developing major diseases.

1993-1998 — Researchers in 40 clinical centers enroll 161,809 postmenopausal women, ages 50 to 79, and begin to measure the approaches and their effect on the incidence of heart disease, breast and colorectal cancer, cognition and fractures. Women are divided into groups with roughly half receiving the treatment and half not.

2002 — The study involving 16,608 women who have not undergone hysterectomies and are taking combined hormone treatments is halted based on health risks that exceeded health benefits for those receiving estrogen and progestin. The 5.2-year study was to last 8.5 years. Researchers had detected seven more adverse events related to coronary artery disease, eight more strokes, eight more pulmonary embolisms and eight more invasive breast cancers in women who received the hormones per 10,000 women compared with the rate for those receiving a placebo. However, six fewer colorectal cancers and five fewer hip fractures also were reported among women taking hormones, suggesting some benefit.

2004 — The memory study involving 2,947 women ages 65 to 79 finds the combined hormone therapy does not protect them against cognitive decline. Further, the study suggests hormone therapy has an adverse effect on cognition among women who had lower cognitive function at the start of the study.

2008 — A follow-up study of women who discontinued the combined hormone therapy concludes that healthy women should not be taking estrogen and progestin to prevent future disease. A second study of estrogen use alone also does not find a benefit. The most important message to women who have stopped hormone therapy is to continue seeing their doctors for prevention and screening of all preventable health conditions.

SOURCES: Journal of the American Medical Association; the National Institutes of Health

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